Frågedatum: 2020-09-21
RELIS database 2020; id.nr. 355, ULIC
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Barn med autism och känslighet för psykofarmaka



Fråga: Jag har hört att barn med autism kan ha extra stor känslighet för psykofarmaka generellt och att det är ”start low, go slow” som gäller. Men det verkar bara gälla vissa barn i den gruppen. Finns vetenskapligt stöd för fenomenet, vad är i så fall bakgrunden, och finns även här forskning om individuella/genetiska skillnader?

Svar: Since to date there is no specific medication developed to autism itself, the psychopharmacologic approach is addressed to some core symptoms, such as hyperactivity, anxiety, depression, etc. Medication is frequently required to decrease the “noise” surrounding autism, including a wide range of maladaptive behaviours and/or associated problems (1-2).

Robust evidence from paediatric, randomized, placebo-controlled trials support the use of second-generation antipsychotics (SGAs), specifically risperidone and aripiprazole, currently the only two medications approved for use in ASD (Autism Spectrum Disorders) children by the FDA, for managing behavioural symptoms, such as severe irritability and aggression in ASD (3-8).

When treating children with ASD using second-generation neuroleptics, a favourable response occurs in 30% to 70% of individuals, with an estimated 25% of patients suffering adverse drug reactions (ADRs). A recently published review aimed to investigate the safety and tolerability profile of antipsychotics in individuals with ASD has shown that antipsychotic-related AEs (particularly CNS events, endocrine and gastro-intestinal disorders) are common among patients with ASD (9).

Risperidone treatment has been shown to cause important weight gain (the mean absolute weight gain having been under 6 months treatment almost 6 kg, contra an expected approximately 2.4 kg) (10).

Risperidone treatment has been also shown to disturb glucose homeostasis and endocrine regulation (particularly leptin) in children and adolescents with ASDs, in a dose- and duration-dependent manner, suggesting leptin and insulin resistance mechanisms (11). Metabolic adverse effects, especially development of type 2 diabetes mellitus should be closely monitored, particularly in individuals receiving high doses and/or long-term risperidone treatment. The same recommendation goes also for other antipsychotics such as aripiprazole and olanzapine (9).

Another critical issue is the co-occurrence of epilepsy in ASD patients which is almost twenty times more frequent when ASD patients are compared with children with typical development. The management of combined epilepsy can represent a challenge for clinicians. Several anti-epileptic drugs can determine an exacerbation of behavioural symptoms, and some psychotropic medications used in ASD patients may lower the seizure threshold (12). For example, risperidone can be safely used up to 3mg/Kg/day, while higher doses can lead to seizures in susceptible patients. Therefore, it’s mandatory to search a treatment strategy with the minor negative impact on this subgroup of patients.

Several papers have addressed the possible role of genetic variation in the safety and efficacy of psychoactive drugs in the therapy of patients with ASD (13-17). The polymorphisms evaluated in these studies were not specifically correlated with ASD, but genetic variants already known to be able to contribute to variability in drugs PK/PD. Furthermore, due to the small sample size of most studies, no definitive conclusions could be drawn.

Recommended reading: ref 7, 9, 12, 13-17.

Referenser:
  1. Ameis S, Szatmari P. Common psychiatric comorbidities in autism spectrum disorder and their assessment. In: Anagnostou E, Brian J, eds.Clinician’s Manual on Autism Spectrum Disorder. Basel, Switzerland: Springer Healthcare; 2015.
  2. Hampson DR, Gholizadeh S, Pacey LK. Pathways to drug development for autism spectrum disorders. Clin Pharmacol Ther. 2012; 91: 189-200.
  3. McCracken J, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med. 2002;347: 314-321.
  4. Shea S, Turgay A, Carroll A, et al. Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics. 2004;114: e634-e641.
  5. Marcus RN, Owen R, Kame L, et al. A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry. 2009; 48:1110-1119.
  6. Owen R, Sikich L, Marcus RN, et al. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics. 2009; 124: 1533-1540.
  7. Correll CU, Kratochvil CJ, March JS. Developments in pediatric psychopharmacology: focus on stimulants, antidepressants, and antipsychotics. J Clin Psychiatry. 2011; 72:655-670.
  8. Chavez B, Chavez-Brown M, Rey JA. Role of risperidone in children with autism spectrum disorder. Ann Pharmacother. 2006; 40(5): 909-916.
  9. Alfageh BH, Wang Z, Mongkhon P, et al. Safety and Tolerability of Antipsychotic Medication in Individuals with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. Paediatr Drugs. 2019;21(3):153-167
  10. Troost PW, Lahuis BE, Steenhuis MP, et al. Long-term effects of risperidone in children with autism spectrum disorders: a placebo discontinuation study. J Am Acad Child Adolesc Psychiatry. 2005; 44(11): 1137-1144.
  11. Srisawasdi P, Vanwong N, Hongkaew Y, et al. Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders. Clin Biochem. 2017; 50(12): 678-685.
  12. Benvenuto A, Battan B, Porfirio MC, Curatolo P. Pharmacotherapy of autism spectrum disorders. Brain Dev. 2013;35(2):119-127.
  13. Youngster I, Zachor DA, Gabis LV, et al. CYP2D6 genotyping in paediatric patients with autism treated with risperidone: a preliminary cohort study. Dev Med Child Neurol. 2014;56(10):990-994.
  14. Hongkaew Y, Medhasi S, Pasomsub E, et al. UGT1A1 polymorphisms associated with prolactin response in risperidone-treated children and adolescents with autism spectrum disorder. Pharmacogenomics J. 2018;18(6):740-748.
  15. Sukasem C, Vanwong N, Srisawasdi P, et al. Pharmacogenetics of Risperidone-Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder. Basic Clin Pharmacol Toxicol. 2018;123(1):42-50.
  16. Correia CT, Almeida JP, Santos PE, et al. Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions. Pharmacogenomics J. 2010;10(5):418-430.
  17. Bishop JR, Najjar F, Rubin LH, et al. Escitalopram pharmacogenetics: CYP2C19 relationships with dosing and clinical outcomes in autism spectrum disorder. Pharmacogenet Genomics. 2015;25(11):548-554.